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Whatever happened to those Neanderthals?

Neanderthal DNA reveals that humans and Neanderthals may have interbred. Or not.

Imagine you're in Europe 40,000 years ago. You are part of a group of Neanderthals happily living in a cave. One day some folks from Africa show up.

There are a number of possibilities here. One is that these new people attack and kill everyone in your tribe. They move into your cave and you are forgotten until the 1850's when your bones are found.

Or there's plenty of food so you each mind your own business. As time goes by, there are more and more of these people. Eventually your descendants slowly die out leaving just these African interlopers.

And finally, maybe we all just get along and have kids together. What comes out of this is some hybrid between the Africans and the Neanderthals.

Which idea is right? No one really knows. What we do know is that Neanderthals ruled Europe for hundreds of thousands of years. Then by 30,000 years ago, they were all gone.

We also know that Neanderthals and our predecessors, Cro-Magnon man, overlapped in Europe for thousands of years. And that they may have lived near one another at the same time. So Neanderthal's disappearance was not quick.

So, did Neanderthals die out or did we interbreed? After so much time this is hard to figure out. One way solve this puzzle is to look for Neanderthal DNA in ours.

The most straightforward way to do this is to look at Neanderthal DNA. And compare it to ours.

Until very recently, this wasn't possible with most of their DNA. So scientists looked at the little snippets they could get a hold of. Or compared African and European DNA to look for differences that might suggest mixing. One group even postulated that red hair came from Neanderthals!

All of these studies suffer from the same thingnot enough Neanderthal DNA to compare human DNA to. New technologies are now making more Neanderthal DNA readable.

This will give data that is much more straightforward than anything available to date. As we are able to look at more of Neanderthal's DNA, we may be able to figure out whether or not there is a little Neanderthal in all of us.

Neanderthal genocide or assimilation

As I said, around 30,000 years ago there were no Neanderthals left in Europe. Either they integrated with Cro-Magnon or died out.

There is strong genetic evidence that we just replaced the Neanderthals in Europe. This evidence comes from the little bit of mitochondrial DNA (mtDNA) that scientists have managed to pull from a few Neanderthal fossils.

Why did they want to look at mtDNA? Because they could. There is a whole lot of it in a cell making it relatively easy to get.

This kind of DNA is a cool relic from our evolutionary past (click here to learn more). Instead of just two copies per cell like our chromosomes, our cells have thousands of copies of mtDNA.

Because there is so much of this DNA, we are able to get some from unlikely sources. Like hair or mammoths. Or Neanderthals.

When scientists looked at this DNA, they found that it was pretty different from modern day European mtDNA. Too different for there to have been much more than 25% mixing.

Of course, if we were 25% Neanderthal, that would be a lot of Neanderthal. However, a recent study looking at the same data suggests that mixing was much lower than this.

The paper claims that if advancing Cro-Magnon men assimilated Neanderthals into the population along the way, then there should be a lot of Neanderthal DNA in all of us. Why?

Imagine that you have a group of Africans and they come up against a group of Neanderthals. These two groups laugh and sing and have babies. Or the occasional Cro-Magnon sneaks out for a tryst with a Neanderthal.

After a while, the valley is getting a little crowded. So this mixed tribe moves over to the next valley where more Neanderthals live. The same thing happens. And no new Africans enter Europe.

As this wave spreads across Europe, there would be an awful lot of Neanderthal DNA in the final mixed group. And yet, we find very little mixing to have happened.

The authors conclude that in order to see the level of mtDNA overlap that we see, there had to be 120 matings or less. In thousands of years. Not much at all.

And yet, other groups assume a lot of mixing. One group decided to compare European and African DNA and look for differences. There were plenty. Too many they claimed to be explained simply by the two groups being apart for a long time.

The best explanation for the level of differences was some mixing between Cro-Magnon DNA and other DNA both in Europe and in Africa. In fact, the best way to explain the data was to say that the mixing rate was around 5%. That is 1 in 20.

The most likely candidate for mixing in Europe was Neanderthal. The authors don't have a most likely candidate for Africa.

The difference in the numbers between these two studies is huge. Of course both of these ideas are speculative and not really based on Neanderthal DNA from the nucleus. They are tied up in models that extrapolate the data back 30,000 years to explain our past.

This is very tricky to do and a small change in the model can have huge effects. Now I do want to re-emphasize that the first group did look at mtDNA. But this kind of DNA makes up just 1/300,000th of our DNA and so it is a pretty small bit to look at.

What if Cro-Magnon didn't find Neanderthal women attractive? But the Neanderthal men loved Cro-Magnon women? Then you might end up with a lot of mixing that is invisible to mtDNA. Why?

Because mtDNA passes directly from mother to children. Dad's mtDNA is destroyed when the sperm fertilizes the egg. The Neanderthal mtDNA would be lost but there would be plenty of Neanderthal nuclear DNA around.

What would really help answer the question is if scientists could look at more Neanderthal DNA. The DNA in the nucleus. And that is just what they have started to do.

More Information

Africans went to Europe andeither merged with or replacedNeanderthal

Did Cro-Magnon have kids with Neanderthals? It is still unclear.

Going nuclear

As I said, scientists have looked at Neanderthal mitochondrial DNA (mtDNA) because there is a lot of it in fossils. But to really figure out if our ancestors mixed with Neanderthals, we probably need to look at nuclear DNA.

And two groups have done just that. These groups looked at up to one million letters of DNA of Neanderthals (out of 6 billion or so).

One group concluded that there was no mixing. The other group concluded that there might have been. To really resolve this, more Neanderthal DNA will need to be sequenced.

Is it possible to read more? To understand this, let's look at how ancient DNA is sequenced.

A few years ago looking at ancient nuclear DNA was impossible. DNA that has been sitting around for 40,000 years takes a bit of a beating.

The DNA tends to end up in little chemically damaged pieces that are hard to deal with by conventional technologies. And there is a whole lot of other DNA contaminating the sample from all of the beasts that have lived there for all of those years.

Two recent technological advances have made looking at this DNA possible. The first is the ability to get lots of DNA from very little.

Now, we have been able to do this for awhile using a technique called PCR. PCR uses special proteins to let you make lots of the DNA you're interested in from very little starting DNA (click here to learn more about PCR).

But while PCR is great, it still needs more DNA then we can get from Neanderthal DNA. In fact, one estimate I saw said that regular old PCR would need pounds of Neanderthal fossils to get enough DNA. There just aren't enough high quality fossils to make this happen.

New methods have become available that allow scientists to get DNA from smaller, more fragmented samples. One example is from a company called 454 Life Sciences (click here to learn more). The 454 method takes all of the pieces of DNA in a sample and let's you read it.

So now you have lots of DNA information, some of which is Neanderthal. And some of which is bacterial or fungal or who knows what else.

How do you separate out the Neanderthal DNA? With computers and fancy computer tools (this process is called metagenomics).

What scientists do is use the DNA information about known animals to pick out the DNA they're interested in. For example, scientists recently sequenced a mammoth's DNA.

They were able to pick out mammoth DNA by looking for DNA that was similar to an elephant's. And to rule out DNA that looked more bacterial or that looked like human contamination. They also could rule out any DNA that was too intact (after thousands of years, the DNA tends to be in very small chunks).

This is the sort of thing that has been done with Neanderthals. And the results are so cool!

It looks like we split from Neanderthals around 500,000 years ago, just as the mtDNA suggested. Humans and Neanderthal are around 99.5% the same. The similarity between any two random people is 99.9%. And between a chimp and a human is 98.7%.

But did Neanderthal and Cro-Magnon mix? One group that looked at ~60,000 bases concluded there probably wasn't any mixing. The second group looked at one million bases and concluded there may have been.

Interestingly, the second group's data was consistent with male Neanderthals interbreeding with female Cro-Magnon. This is just the sort of liaison that would be invisible in mtDNA.

So we don't know the answer yet because there is still too little of the DNA sequenced to get a definitive answer. A lot more sequencing will be needed to nail this down.

But there may be light at the end of the tunnel. As more and more DNA is sequenced from many different fossils, the truth should be revealed. Did we wipe them out? Or do Europeans have a bit of Neanderthal in them.

This project was supported by the Department of Genetics, Stanford School of Medicine. Its content is solely the responsibility of the authors and does not necessarily represent the official views of Stanford University or the Department of Genetics.